Oxymetazoline For The Treatment Of Ano-Rectal Disorders

ABSTRACT

Methods for treating fecal incontinence by administering to a subject in need thereof compositions including oxymetazoline as an active ingredient. Kits including compositions of oxymetazoline suitable for topical application, for the treatment of fecal incontinence.

FIELD OF THE INVENTION

The present invention provides methods for treating ano-rectaldisorders, specifically, fecal incontinence, by administering to asubject in need thereof compositions comprising oxymetazoline as anactive ingredient. The present invention further provides kitscomprising compositions of oxymetazoline suitable for topicalapplication, for the treatment of ano-rectal disorders.

BACKGROUND OF THE INVENTION

Fecal incontinence is a common disorder in men and women, though moreprevalent in women. The mechanisms causing anal incontinence usuallyinvolve reduced resting tone of the external and internal analsphincters, and damage in the levator ani muscles, especially, thepuborectalis muscle.

Conventional treatments of fecal incontinence include pelvic floorrehabilitation by exercises or surgical interventions and drug therapy.Biofeedback training is one of the treatments involving musclestrengthening exercises to improve anal canal resting and squeezepressure, and to improve the symmetry of anal canal function.

Drug therapy is mostly directed to improve stool consistency andincludes the use of morphine and loperamide among others. Drug therapyalso includes administration of codeine phosphate to reduce gut motility(peristalsis), or laxatives to soften stools and relieve constipation.Therapy with sodium valproate was found to be useful in the treatment ofminor incontinence after ileoanal anastomosis (Kusunoki et al., Surgery,1990, 107:311-315). It was also shown that in vitro contractile responseof the internal anal sphincter to noradrenaline is decreased inincontinence (e.g. Speakman et al., Digestive Diseases and Sciences,1993, 38(11):1961-1969). Therapy with Solesta™, a viscous biocompatiblebulking agent, was shown to be superior to sham treatment, resulting in50% reduction of incontinence episodes.

Yet, the most common form of treatment is surgical repair, such as, thecreation of a neo-sphincter which involves grafting on muscle from otherparts of the anus, or a colostomy. However, success rates of surgeries,such as external anal sphincteroplasty, are around 50% or less.

Recent drug therapies directed to increase the anal resting pressure ofa patient having a reduced anal resting pressure are disclosed in U.S.Pat. Nos. 6,635,678 and 7,781,444. Therapy according to thesepublications involves topical administration in and/or around the analcanal of a patient a composition comprising at least 5% w/w of anα-adrenergic agonist, particularly, noradrenalin, methoxamine andphenylephrine. However, according to these publications no significantincrease in the maximum resting pressure was observed for phenylephrineconcentrations below 10%, where the recommended concentrations are of10-30% phenylephrine.

Oxymetazoline is an α-adrenergic agonist commercially known for long asa topical decongestant in the form of nasal sprays, such as, Afrin™(e.g. U.S. Pat. No. 6,824,762). Topical application of oxymetazoline wasalso suggested for treating sympathetically maintained pain inperipheral tissues (e.g. RE 41,998), for reducing or eliminating painassociated with a syringe, needle stick, or lancet stick as avasoconstrictor combined with local anesthetic (e.g. U.S. Pat. No.7,883,488) and for ameliorating telangiectasias (U.S. Pat. No.7,838,563) among other uses.

To date, no particularly efficient drug therapy for treating ano-rectaldisorders, such as, fecal incontinence is known.

SUMMARY OF THE INVENTION

The present invention provides compositions, methods and kits fortreating ano-rectal disorders, such as, fecal incontinence. Morespecifically, the invention is drawn to the advantageous topical use ofoxymetazloine and salts or derivatives thereof, for the treatmentano-rectal disorders.

The present invention is based in part on the unexpected increase inresting anal pressure obtained upon local administration of relativelylow concentrations of oxymetazloine. Surprisingly, the inventors of thepresent invention have found that unlike other α-adrenergic agonists,specifically, pheynilephrine, which either have a short term effect ordoes not exhibit a pronounced effect on a resting anal pressure, localadministration of oxymetazoline provides a long term pronounced increaseof the resting anal pressure. Advantageously, the improved effect ofoxymetazoline was exerted by only 1 mg (0.1%) of oxymetazoline, a dosethat is more than one order of magnitude lower than the less effectivedoses of phenylephrine (40 mg and 80 mg) tested by the inventors.Moreover, the dose of oxymetazoline which was found effective is lowerby more than 2 orders of magnitude from the prior art doses of otherα-adrenergic agonists (e.g. U.S. Pat. No. 6,635,678 and U.S. Pat. No.7,781,444 which recommend using doses of 10% to 30% of phenylephrine forobtaining a significant increase in the mean resting pressure). The useof such low concentrations of oxymetazoline is particularly advantageousin view of the concentration dependent cardiovascular side effects knownto be exerted by α-adrenergic agonists.

Another advantage exerted by the method of the invention is in therelease of patients suffering from anal leakage from the need to undergomajor surgery. Thus, oxymetazoline's effect in increasing the restinganal pressure addresses the desired need for non-invasive effectivetherapeutic means for the treatment of ano-rectal disorders.

Accordingly, in a first aspect the present invention provides a methodfor treating an ano-rectal disorder, comprising administering to apatient in need thereof a pharmaceutical composition comprising as anactive ingredient oxymetazoline or a pharmaceutically acceptable salt orderivative thereof, wherein the concentration of the active ingredientis about 0.1%.

The term “about 0.1%” as used herein refers to concentrations within therange of 0.05% to 1%. That range was found effective for increasing theanal resting pressure of a patient in need thereof and at the same timesafe in terms of cardiac disorders.

According to one embodiment, the active ingredient is oxymetazolinehydrochloride.

According to another embodiment, the concentration of the activeingredient is within the range of 0.05% to 1%. According to a particularembodiment, the active ingredient is oxymetazoline hydrochloride and theconcentration of oxymetazoline hydrochloride is within the range of0.05-1%, or within the range of 0.08-0.8% or about 0.1%. Eachpossibility is a separate embodiment of the invention.

According to yet another embodiment, treating according to the presentinvention is effective for at least 4 hours.

According to yet another embodiment, the composition further comprisesat least one carrier, diluent, excipient or combinations thereof. Eachpossibility is a separate embodiment of the invention.

According to yet another embodiment, the pharmaceutical composition isselected from the group consisting of: long acting, controlled releaseformulation, a sustained release formulation, bioadhesive formulation,mucoadhesive formulation, and a slow release formulation. Eachpossibility is a separate embodiment of the invention.

According to yet another embodiment, the ano-rectal disorder is selectedfrom the group consisting of: fecal incontinence, anorectal fistula,rectal prolapsed and ileal pouch-anal anastomosis. Each possibility is aseparate embodiment of the invention.

According to yet another embodiment, the pharmaceutical composition isapplied locally to any one or more of the locations selected from thegroup consisting of the internal anal sphincter, external analsphincter, inside the anal canal and the anoderm. Each possibility is aseparate embodiment of the invention.

According to yet another embodiment, the composition is in a dosage formselected from the group consisting of: gel, ointment, mousse, cream,paste, spray and suppository. Each possibility is a separate embodimentof the invention.

According to yet another embodiment, treating an ano-rectal disorder isselected from the group consisting of: preventing the occurrence of anano-rectal disorder, reducing or preventing fecal incontinence,increasing the resting anal pressure, maintaining a high resting analpressure for at least one hour, strengthening the anal sphincter musclesthereby preventing leakage and improving the rectum sensation. Eachpossibility is a separate embodiment of the invention.

It is to be understood that “high resting anal pressure” as used hereinis not necessarily limited to a particular value or measuring means butrather refers to an anal squeeze pressure required to prevent fecalleakage.

According to yet another embodiment, the method further comprisesadministering one or more additional therapeutic agent in combinationwith oxymetazoline. According to yet another embodiment, the additionaltherapeutic agent is selected from the group consisting of: nitric oxide(NO) synthase inhibitor, prostaglandin F2α, dopamine, morphine, opium,loperamide, β-blockers, sodium valproate, codeine phosphate and5-Hydroxytryptamine. Each possibility is a separate embodiment of theinvention.

According to yet another aspect, the present invention provides a methodfor treating fetal incontinence comprising administering to a subject inneed thereof a composition comprising as an active ingredientoxymetazoline.

According to yet another aspect, the present invention provides a methodfor treating an ano-rectal disorder comprising administering to asubject in need thereof a combined therapy comprising oxymetazoline or apharmaceutically acceptable salt thereof and an additional therapeuticagent selected from the group consisting of: NO synthase inhibitor,prostaglandin F2α, dopamine, morphine, opium, loperamide, β-blockers,sodium valproate, codeine phosphate and 5-Hydroxytryptamine. Eachpossibility is a separate embodiment of the invention.

According to one embodiment, the oxymetazoline and the additionaltherapeutic agent are administered in fixed intervals, at variableintervals, sequentially or concurrently. Each possibility is a separateembodiment of the invention. According to yet another embodiment theoxymetazoline and the additional therapeutic agent are administered in asingle dosage form.

According to yet another embodiment, the oxymetazoline is oxymetazolinehydrochloride.

According to yet another embodiment, the concentration of oxymetazolinehydrochloride is within the range of 0.05 to 1%.

According to yet another embodiment, the combined therapy is effectivefor at least 4 hours.

According to yet another aspect, the present invention provides a kitfor treating an ano-rectal disorder in a subject in need thereofcomprising

(a) a first dosage form comprising oxymetazoline or a pharmaceuticallyacceptable salt or derivative thereof, wherein the concentration ofoxymetazoline in the first dosage form is within the range of 0.05 to1%; and(b) means for storing the dosage form.

According to one embodiment, the means for storing the dosage form,include, but are not limited to, a container suitable for long storageand blister packaging for pharmaceuticals, among others.

According to another embodiment, the kit further comprises a seconddosage form comprising a therapeutic agent selected from the groupconsisting of: NO synthase inhibitor, prostaglandin F2α, dopamine,morphine, opium, loperamide, β-blockers, sodium valproate, codeinephosphate and 5-Hydroxytryptamine. Each possibility is a separateembodiment of the invention. According to another embodiment, the firstand second dosage forms are contained in a single container. Accordingto yet another embodiment, the first dosage form and the second dosageform are contained in separate containers. According to yet anotherembodiment, the first dosage form comprises oxymetazoline hydrochloride.

According to yet another aspect, the present invention provides apharmaceutical composition comprising as an active ingredient anoxymetazoline or a pharmaceutically acceptable salt or derivativethereof for use in the treatment of an ano-rectal disorder, wherein theconcentration of the active ingredient is within the range of 0.05% to1%.

According to some embodiments, the pharmaceutical composition furthercomprises one or more additional therapeutic agent in combination withoxymetazoline. According to yet another embodiment, the additionaltherapeutic agent is selected from the group consisting of: nitric oxide(NO) synthase inhibitor, prostaglandin F2α, dopamine, morphine,loperamide, β-blockers, sodium valproate, codeine phosphate and5-Hydroxytryptamine.

According to yet another aspect, the present invention provides apharmaceutical composition for use in the treatment of an ano-rectaldisorder in combination with an additional therapeutic agent selectedfrom the group consisting of: NO synthase inhibitor, prostaglandin F2α,dopamine, morphine, loperamide, β-blockers, sodium valproate, codeinephosphate and 5-Hydroxytryptamine.

According to yet another aspect, the present invention provides acombined therapy comprising the pharmaceutical composition of thepresent invention, and an additional therapeutic agent selected from thegroup consisting of: NO synthase inhibitor, prostaglandin F2α, dopamine,morphine, loperamide, β-blockers, sodium valproate, codeine phosphateand 5-Hydroxytryptamine for use in the treatment of an ano-rectaldisorder.

According to one embodiment, the active ingredient is oxymetazolinehydrochloride.

According to yet another embodiment, the ano-rectal disorder is selectedfrom the group consisting of: fecal incontinence, anorectal fistula,rectal prolapsed and ileal pouch-anal anastomosis. According to yetanother embodiment, the ano-rectal disorder is fecal incontinence.

According to yet another embodiment, the composition is in a dosage formselected from the group consisting of: gel, cream, paste, spraysuppository, mousse, emollient, powder, solution, suspension and foam.

According to yet another embodiment, the concentration of theoxymethazoline is within the range of 0.05% to 1%. According to yetanother embodiment, the concentration of oxymethazoline is within therange of 0.08 to 0.8%.

According to yet another embodiment, the pharmaceutical composition iseffective for at least 4 hours.

According to yet another embodiment, the oxymetazoline and theadditional therapeutic agent are administered in fixed intervals, atvariable intervals, sequentially or concurrently. According to anotherembodiment, the oxymetazoline and the additional therapeutic agent arein a single dosage form.

Further embodiments, features, advantages and the full scope ofapplicability of the present invention will become apparent from thedetailed description and drawings given hereinafter. However, it shouldbe understood that the detailed description, while indicating preferredembodiments of the invention, are given by way of illustration only,since various changes and modifications within the spirit and scope ofthe invention will become apparent to those skilled in the art from thisdetailed description.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 represents the mean relative resting anal pressure exerted bytopical application of 1 mg oxymetazoline (solid line), 40 mgphenylephrine (dotted line) and 80 mg phenylephrine (broken line).

DETAILED DESCRIPTION OF THE INVENTION

Fecal incontinence is a disorder common to both genders although morecommon in women after childbirth, presumably as a result of trauma topelvic floor muscles, supporting fascia and nerves. Fecal incontinenceaffects an estimated 7.6 percent of women between the ages of 30 to 90.This prevalence increases with age, affecting 3.6 percent of womenbetween the ages of 30 to 39 and 15.2 percent of women between the agesof 80 to 90.

Fecal incontinence may occur as the result of several mechanisms,including direct damage to the internal or external anal sphincters(from iatrogenic episiotomy or spontaneous lacerations during vaginaldelivery), or to the levator ani muscles. It may also result fromindirect injury of these muscles through denervation of the nerves thatsupply these muscles. Treatment of this problem has centered on pelvicfloor rehabilitation, dietary changes, or surgical correction. Asdetailed below, surgery has been used to treat specific defects in theanal sphincters, such as, external anal sphincteroplasty. Success ratesof only 50% or less are generally reported for these procedures onlong-term follow-up.

It has been shown that two thirds of patients with idiopathic fecalincontinence had a decreased anal resting pressure resulting from anabnormal internal sphincter function. In many incontinent patients, theinternal anal sphincter was found to be abnormally thin, while othershad an external anal sphincter defect.

The conservative interventions for treating fecal incontinence consistmainly of changes in lifestyle (sport, work, giving up smoking,modification to the diet and fluid intake); measures of assistance withdaily activities (adaptation of clothing, absorbent products, bags,stoppers, adaptation of the fitting out of toilets, control of odor,skincare); intestinal control and a retraining programs (planning forgoing to the toilet, resisting urgent need, behavior modification,rectal irrigation, digital stimulation or the like, abdominal massage);and functional readaptation by stimulation (and/or pelvic or sphincterexercises). This conditioning method, which uses visual, verbal orauditory signals, improves rectal sensation and rectoanal coordination,and brings about contraction of the external anal sphincter. The successrates of various series range from 40% to 85%, which rates couldprobably be predicted by the patient's motivation and the cause of thepathology rather than by the duration of fecal incontinence, manometricor endoanal ultrasound measurements or else the functional readaptationtechnique used.

Although the conservative measures are simple to implement, they areoften of limited effectiveness.

Several techniques making use of medical devices exist which can benefitpatients suffering from fecal incontinence. For example, the “protoncontinence” device (Incontinence Control Devices, Inc., Kingwood, Tex.)is a flexible catheter with a photosensor and a balloon, which can beinserted into the rectum in order to send a signal warning of thearrival of stools. This device has shown an improvement in continence incertain patients. Moreover, submucosal injections of a wide variety ofagents have been used to increase internal anal sphincter tone(silicone, silicone-based agents, this include, carbon-coated beads,carbon-coated zirconium oxide beads (Durasphere™), autologous fat andcollagen crosslinked with glutaraldehyde, polytetrafluoroethylene. Thesedevices have shown a partial symptomatic improvement in resting analpressure and in continence.

The Secca™ procedure (Curon Medical, Inc., Sunnyvale, Calif.) usesradiofrequency energy controlled by the temperature of the anal canaland of the distal rectum in order to create scarring of the externalanal sphincter and tissue fibrosis. In a multicentre prospective studyby Efron et al. an improvement in fecal incontinence and in the qualityof life with disappearance of symptoms in 60% of patients. Takahashi etal. have reported similar results after a follow-up of patients for 2years.

Another treatment for faecal incontinence is sacral nerve stimulation(SNS) which, by “neuromodulating” the somatic voluntary nerves and theafferent and efferent autonomic nerves, makes it possible to stimulateboth the somatic and the autonomic innervation of the pelvic organs andof the anorectal region, through the sacral and pudendal nerves. Theresults published with this procedure are encouraging, with a markedimprovement in continence of up to 100% and restoration of completecontinence in 41% to 75% of cases.

All these procedures have certain effectiveness, but their use isrestrictive.

Drug treatments for fecal incontinence are limited to anti-diarrheaagents and to laxatives, enemas and suppositories, which make itpossible to evacuate the bowel. At low dose, amitryptiline (tricyclicanti-depressant), via its anticholinergic and serotoninergic activities,could also improve continence. On the other hand, no medicament thatacts on sphincter tone is currently registered specifically for thetreatment of fecal incontinence.

The viscous bulking agent, Solesta™, has been suggested for treatingfecal incontinence in adult patients who have failed conservativetherapy. Solesta™ is injected in the deep submucosal layer in theproximal part of the high pressure zone of the anal canal, about 5 mmabove the dentate line. A total of four submucosal injections of 1 mLSolesta™ are administered at each treatment session. However, Solesta™was shown to be superior over placebo in 50% of the treated subjects.

At the current time, the only alternative in patients suffering fromexternal sphincter disorders but without a neurological condition(intact pudendal nerves) is, after failure of conservative therapies,surgery. An artificial anal sphincter has been used to bypass thesemuscles, though this surgery involves fairly extensive dissection andrequires the patient to depress a subcutaneous valve which temporarilydeflates the sphincter cuff and allows voluntary defecation. Thisprocedure is performed in very few centers in the U.S., and even inexperienced hands, complications occur frequently.

Dynamic graciloplasty, which involves mobilization and wrapping of thegracilis muscle around the anorectum is another accepted procedurealthough is remains complex and requires extensive experience to obtaingood results. More recently, sacral nerve stimulation has been used withsome success to treat fecal incontinence, though the mechanism ofsuccess in these patients remains unclear, and may not be appropriate inwomen with obvious anatomic abnormalities, such as anal sphincter orlevator muscle disruptions.

Further discussion of the innervations and control of the internal analsphincter and drugs which can increase or decrease the normal analresting pressure, is discussed in various text books (e.g.,Coloproctology and the Pelvic Floor, Butterworths, second edition, 1992,Chapter 3, p. 37-53; Automic Control of Internal Anal Sphincter).Implantations of devices intended to improve fecal incontinence, forexample, microstimulators for implantation thereof in the anal sphincterfor treating fecal incontinence, are disclosed for example, in U.S. Pat.No. 7,871,415.

Other than anal incontinence, many women report on symptoms of boweldysfunction, such as constipation and incomplete bowel emptying. Forsome women, these symptoms are due to either an anterior rectocele (ahernia of the rectum into the vaginal canal), or due to a defect in thelevator ani muscles, which results in descent of the levator plateand/or perineum with abdominal straining. In addition, patients may benoted to have a defect in the posterior aspect of the rectum, or aposterior rectocele. There are very few treatment options for thiscondition, though retrorectal levatorplasty has been used in the past.In this procedure, an incision is made between the anus and the coccyxand the levator muscles are exposed bilaterally. Sutures are then placedin the levator muscles to plicate them together in the midline. Pelvicorgan prolapse is a condition where organs, such as the uterus, therectum, or the bladder, fall down or slip out of place within a person'sbody. It is commonly used in reference to organs protruding through awoman's vagina, but prolapse may occur within men as well.

The method of the invention appear to treat ano-rectal disorders, suchas, fecal incontinence by increasing the resting pressure of theinternal anal sphincter using topical administration of the α-agonistoxymetazoline or salts thereof.

Alpha-agonists are known to cause side effects, of particular alert arecardiovascular disorders. Because alpha1-agonists produce systemicvasoconstriction, the effort on the heart increases. If the coronarycirculation is impaired, as in patients with coronary artery disease,the decrease in myocardial oxygen supply/demand ratio can precipitateangina. In view of the above, the inventors of the present inventionsearched for an α-agonist that does not exert a cardiac side effect,while being effective in increasing the resting anal pressure.Surprisingly, oxymetazoline was found the best candidate as it waseffective in low doses of about 0.1% but did not induce any changes inthe diastolic blood pressure, systolic blood pressure or in the heartrate (see Example 2).

Oxymetazoline, also known as3-(4,5-dihydro-1H-imidazol-2-ylmethyl)-2,4-dimethyl-6-tert-butyl-phenol,is an α-adrenergic agonist commercially available over the counter inits hydrochloride salt form, as a topical decongestant in the form ofnasal sprays. Oxymetazoline seems to exert its therapeutic action bynonselectively agonizes adrenergic receptor, which are widely expressedin vascular beds, thereby causing vasoconstriction. Vasoconstriction ofvessels results in relief of nasal congestion by increasing the diameterof the airway lumen; and by reducing fluid exudation from postcapillaryvenules.

Methods for measuring resting anal pressure include manometry (todetermine the maximum resting anal pressure). In this method awater-filled microballoon system connected to a plastic rigid catheterand transducer and then to a pen chart recorder or pressure sensitiveelectrodes, which are connected to an amplifier/monitor, is used.Maximum resting anal pressure is obtained using a station pull throughtechnique where a catheter is taped to the buttock and a continuousreading being performed until a steady anal pressure is achieved. Aftera drug is administered, continuous pressure readings may be taken, forexample, between 15 and 31 minutes. Pulse rate and blood pressure may bemonitored and the subject may be questioned for adverse effects, suchas, headache, anxiety, palpitations and abdominal or anal pain.

A preferred oxymetazoline according to the present invention is anoxymetazoline salt, such as, oxymetazoline hydrochloride salt.Oxymetazoline hydrochloride has the chemical name6-tert-butyl-3-(2-imidazolin-2-ylmethyl)-2,4-dimentylphenolhydrochloride (CAS Registry No. 2315-02-8). According to U.S. PatentApplication, Publication No. 2009/0281156, by lowering the pH offormulations containing oxymetazoline HCl, photodegradation level ofoxymetazoline HCl is significantly reduced, even in the presence ofdestabilizing excipients, such as PVPs or PEGs.

The composition further comprises a least one carrier, diluent,excipient or combinations thereof.

Oxymetazoline is soluble in aqueous and non aqueous media andaccordingly, oxymetazoline solution may contain an aqueous carriercomprising: 70 to 90% by weight/volume of water; 0.10 to 5.00% byweight/volume of an aromatic alcohol; 0.01 to 0.3% by weight/volume of anon-mercurial antimicrobial preservative; 0 to 10% by weight/volume of amoisturizing agent; a sufficient amount of a pharmaceutically acceptablebuffer to maintain the pH of the composition within the range of about4.00 to 6.00; and/or other agents as deemed necessary to enhance flavoror to enhance the functional capabilities of the primary agent.

In one embodiment, the pharmaceutical composition is formulated as longacting, controlled release formulation. In another embodiment, thepharmaceutical composition is formulated as a sustained releaseformulation. In another embodiment, the pharmaceutical composition is abioadhesive formulation or a mucoadhesive formulation.

Controlled or sustained release formulations allowing for extended orslow release of the active components over a predetermined time periodmay be formulated using procedures known in the art. Alternatively, thecompositions may be formulated as immediate release formulations.

Techniques for formulation and administration of drugs may be found in“Remington's Pharmaceutical Sciences,” Mack Publishing Co., Easton, Pa.,latest edition, which is incorporated herein by reference.

The inert ingredients (e.g. excipient or a carrier) and manner offormulation of the pharmaceutical compositions are conventional. Theactive compound is formulated into pharmaceutical compositions andadministered in a variety of forms appropriate for the method of theinvention including, but not limited to liquid, semisolid, powders,suppositories, sprayable solutions, gel, ointment, mousse, cream orpaste.

Suitable excipients include, but are not limited to lactose, dextrose,sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate,alginates, tragacanth, gelatin, calcium silicate, microcrystallinecellulose, polyvinylpyrrolidone, cellulose, water, syrup, andmethylcellulose.

The formulations may additionally include lubricating agents, such as,talc, magnesium stearate and mineral oil; wetting agents; emulsifyingand suspending agents; preserving agents such as methyl- and propylhydroxybenzoates.

Additional excipients that are particularly suitable for the manufactureof suppositories, include, but are not limited to, coconut oil, cocoabutter, polyethylene glycol, propylene glycol, glycerinated gelatin,hydrogenated vegetable oil, fatty acid esters of a polyethylene glycols,glycolsurfactant polyethylene glycol, a polyoxyethylene derivatives ofsorbitan monostearate or polyoxyl-40 stearate, and combinations thereof.Each possibility is a separate embodiment of the invention.

The liquid forms in which the compositions of the present invention maybe incorporated, for administration to internal anal sphincter, externalanal sphincter, inside the anal canal and the anoderm, include aqueoussolutions, aqueous or oil suspensions, and similar pharmaceuticalvehicles. The procedure for introducing the compositions of theinvention into the rectum and colon may involve use of enema devices.

Suitable pharmaceutical compositions for topical application accordingto the invention include, may be in the form of ointment, gel, mousse,drops, emollient, powder, solution, suspension, foam, suppository,cream, lotion, paste, spray, aerosol or oil. Examples of suitablevehicles include, but are not limited to aquaphor, neobase, propyleneglycol, glycerin and the like. Combinations of two or more of thesevehicles can also be used. Each possibility is a separate embodiment ofthe invention.

Other suitable forms for topical application of the pharmaceuticalcompositions of the invention include bioadhesive such as mucoadhesiveformulations. Adhesion of formulation to the mucosal tissue creates anintimate and prolonged contact at the administration site, resulting inenhanced absorption and controlled release. Mucoadhesive formulationsusually include mucoadhesive polymers, such as, cross-linkedpoly(acrylic acid), glyceryl monooleate, polyvinyl chloride and glycerylmonolinoleate. More information on mucoadhesive formulations may befound in Edsman et al. (JPP, 2005, 57: 3-22) among others.

Preferred excipients include propylene glycol, polyethylene glycol andthe like, as these compounds prevent bacterial growth in thecomposition.

In one embodiment, the inventive composition is provided as a cream,sometimes referred to as an emulsion. Suitable creams may comprise, inaddition to the active ingredient, a stiffening agent, a releasemodifier and a polar solvent (water or a substitute thereof).

The stiffening agent used for creams may comprise a fatty alcohol,having a hydrocarbon chain containing 16 to 18 carbon atoms and having amelting point in pure state of about 45 to 65° C. Alternatively, thestiffening agent may be cetyl alcohol, stearyl alcohol, or cetostearylalcohol, preferably stearyl alcohol. Each possibility is a separateembodiment of the invention.

In such creams, the release modifier may comprise a fatty alcohol, afatty alcohol glycol ether, or a fatty acid sorbitane ester, having ahydrocarbon chain containing 12 to 18 carbon atoms and having a meltingpoint in pure state of about −10 to 40° C.

Alternatively, the release modifier may be dodecanol, tetradecanol,palmitoyl alcohol, oleyl alcohol, linoleyl alcohol, polyoxyethylenelauryl ether, polyoxyethylene myristyl ether, polyoxyethylene cetylether, polyoxyethylene stearyl ether, sorbitane monolaurate, sorbitanemonooleate, or glyceryl monooleate, preferably oleyl alcohol. Eachpossibility is a separate embodiment of the invention.

In a preferred cream, the release modifier may comprise a fatty alcohol,having a hydrocarbon chain containing 12 to 18 carbon atoms and having amelting point in pure state of about −10 to 40° C. Alternatively, therelease modifier may be dodecanol, tetradecanol, palmitoyl alcohol,oleyl alcohol, or linoleyl alcohol, preferably oleyl alcohol.

The release modifier may be present in the cream in an amount of about 1to 12% by weight, preferably about 2 to 10% by weight, based on theweight of the composition.

In the cream, water or a substitute thereof is present. Suitablesubstitutes are glycerol or ethanol. Each possibility is a separateembodiment of the invention.

In another embodiment, the inventive composition is present as anointment. Such ointment may comprise, in addition to the activeingredient, the stiffening agent and the release modifier, and a polarsolvent as described above. Each possibility is a separate embodiment ofthe invention.

In an ointment, the stiffening agent may comprise a fatty alcohol,having a hydrocarbon chain containing 16 to 18 carbon atoms and having amelting point in pure state of about 45 to 65° C. Alternatively, thestiffening agent may be cetyl alcohol, stearyl alcohol, or cetostearylalcohol, preferably stearyl alcohol. Cetomacrogol emulsifying wax is asource of cetostearyl alcohol and thus a convenient way of providing astiffening agent in the ointment.

The release modifier may comprise a fatty alcohol, a fatty alcoholglycol ether, a fatty acid alkyl ester, a fatty acid glycerol ester, ora fatty acid sorbitane ester, having a hydrocarbon chain containing 12to 18, carbon atoms and having a melting point in pure state of about−10 to 40° C. Alternatively, the release modifier may be dodecanol,tetradecanol, palmitoyl alcohol, oleyl alcohol, linoleyl alcohol,polyoxyethylene lauryl ether, polyoxyethylene myristyl ether,polyoxyethylene cetyl ether, polyoxyethylene stearyl ether, sorbitanemonolaurate, sorbitane monooleate, or glyceryl monooleate, preferablyoleyl alcohol. Each possibility is a separate embodiment of theinvention.

The release modifier may also comprise a fatty alcohol, a fatty alcoholglycol ether, or a fatty acid sorbitane ester, having a hydrocarbonchain containing 12 to 18 carbon atoms and having a melting point inpure state of about −10 to 40° C.

In some embodiments, the release modifier of the oinment may bedodecanol, tetradecanol, palmitoyl alcohol, oleyl alcohol, or linoleylalcohol. Each possibility is a separate embodiment of the invention.

The release modifier may be present in the ointment in an amount ofabout 5% to 15% by weight, or about 8% to 12% by weight, based on theweight of the composition.

When a topical preparation is an ointment, cream, gel or paste in atube, the instructions for use may recommend an appropriate amount to beused, for example, to squeeze about 2-3 cm of preparation from the tube.A topical preparation may be provided in a container that comprises apump and metered dosing device to assist correct dosing. In general,from about 0.5 to about 3 ml, for example, about 1 ml, is a suitablevolume of a cream, gel or ointment for topical application. However,when applying a topical preparation, especially when using the finger,it is often difficult to administer a precise dose. Use of an applicatormay give more precise dosing.

The instructions for use of the pharmaceutical composition of thepresent invention should indicate the recommended site of application,for example, whether the preparation should be applied to the skinaround the anus or whether the preparation should also be inserted intothe anus. Preferably, the instructions for use of the pharmaceuticalcomposition of the present invention should further indicate therecommended dose and treatment regimen.

In one embodiment, the composition of the invention may comprise asidefrom oxymetazoline, an agent selected from the group consisting of:benzalkonium chloride, benzylalcohol, edentate disodium,carboxymethylcellulose sodium, microcrystalline cellulose, polyethyleneglycol, povidone, sodium phosphate dibasic, sodium phosphate monobasicand water. Each possibility is a separate embodiment of the invention.

The composition of the invention is intended for the treatment of anyano-rectal disorder, including, but not limited to, fecal incontinence,anorectal fistula, rectal prolapsed and ileal pouch-anal anastomosis.Each possibility is a separate embodiment of the invention.

The ileal pouch-anal anastomosis, also known as an ileo-anal pouch,restorative proctocolectomy, ileal-anal pullthrough, j-pouch, s-pouch,w-pouch or an internal pouch, is an internal reservoir constructed forpatients who have had their large intestine surgically removed due todisease or injury.

The ileal pouch-anal anastomosis is usually situated where the rectumwould normally be and is formed by folding loops of small intestine (theileum) back on themselves and stitching or stapling them together. Theinternal walls are then removed thus forming a reservoir. The reservoiris then stitched or stapled into the perineum where the rectum was.

Diseases and conditions of the large intestine which may requiresurgical removal of the large intestine include: ulcerative colitis,crohn's disease, familial adenomatous polyposis, colon cancer and toxicmegacolon.

The term “treating an ano-rectal disorder” as used herein refers to anyone of the following: preventing the occurrence of an ano-rectaldisorder, reducing or preventing fecal incontinence, increasing theresting anal pressure, maintaining a high resting anal pressure for atleast one hour, strengthening the anal sphincter muscles therebypreventing leakage, improving the rectum sensation, increasing the toneof the pyloric sphincter, increasing the tone of smooth muscle of thegastrointestinal tract and increasing the tone of a sphincter of thegastrointestinal tract. Each possibility is a separate embodiment of theinvention.

It is to be understood that “high resting anal pressure” as used hereinis not necessarily limited to a particular value or measuring means butrather refers to an anal squeeze pressure required to prevent fecalleakage.

The method of the invention may further comprise combined therapy,namely, a combination of two therapeutic compounds for treating apatient afflicted with an ano-rectal disorder. Thus, the method of theinvention may further include administering at least one additionaltherapeutic agent in combination with oxymetazoline. The additionaltherapeutic agent may include any one or more of the following agents:nitric oxide (NO) synthase inhibitor, prostaglandin F_(2α), dopamine,morphine, loperamide, β-blockers, sodium valproate, codeine phosphateand 5-Hydroxytryptamine. Each possibility is a separate embodiment ofthe invention.

Examples of suitable prostaglandin F_(2a) include dinoprost andcarboprost. Examples of suitable NO synthase inhibitors includeN^(G)-monomethyl-L-arginine (L-NMMA), and N^(G)-nitro-L-arginine methylester (L-NAME).

The prostaglandins, along with thromboxanes and leukotrienes are allderived from 20-carbon polyunsaturated fatty acids and are collectivelytermed eicosanoids. F_(2α). prostaglandins are derived in vivo from theendoperoxide prostaglandin H₂ which is in turn derived fromleukotrienes. Clinically, F_(2α) prostaglandins, such as, dinoprost andcarboprost, are used as uterine stimulants in the termination ofpregnancy, missed abortion or the induction of labor.

The present invention further encompasses methods for treating anano-rectal disorder by administering to a subject in need thereof acombined therapy comprising oxymetazoline or a pharmaceuticallyacceptable derivative or salt thereof and an additional therapeuticagent selected from the group consisting of: NO synthase inhibitor,prostaglandin F_(2α), dopamine, morphine, loperamide, β-blockers, sodiumvalproate, codeine phosphate and 5-Hydroxytryptamine.

In some embodiment, the oxymetazoline and the additional therapeuticagent are administered in fixed intervals, at variable intervals,sequentially or concurrently. Each possibility is a separate embodimentof the invention. Furthermore, the oxymetazoline and the additionaltherapeutic agent may be administered in a single dosage form.

Whether administered alone or in combination with another activeingredient, the therapeutic effect of oxymetazoline on the ano-rectaldisordered is maintained for at least 4 hours, or even for at least 5hours.

According to further aspects the present invention provides kitssuitable for use in methods of treating ano-rectal disorders, in asubject. Thus, in another embodiment, there is provided a kit comprising(a) a first dosage form comprising oxymetazoline or a pharmaceuticallyacceptable derivative or salt thereof; and (b) container means tocontain the dosage form.

The kit may further comprise a second dosage form comprising atherapeutic agent selected from the group consisting of: NO synthaseinhibitor, prostaglandin F2α, dopamine, morphine, loperamide,β-blockers, sodium valproate, codeine phosphate and 5-Hydroxytryptamine.

According to some embodiments the first and second dosage forms arecontained in a single container. According to other embodiments thefirst dosage form and the second dosage form are contained in separatecontainers.

The effective concentration of oxymetazoline for treating ano-rectaldisorder is usually within the range of 0.05 to 1%, or within the rangeof 0.08 to 0.8%, or about 0.5% or about 0.1%.

Examples of dosage forms for the pharmaceutical composition of thepresent invention are described above. For rectal administration, dosageforms include, for example, tablets, capsules and suppositories. Ametered dosing device may be provided, for example, a pump device, fordosing a predetermined volume of a topical composition, for example, acream, ointment or gel.

The following examples are presented in order to more fully illustratesome embodiments of the invention. They should, in no way be construed,however, as limiting the broad scope of the invention.

EXAMPLES Example 1 The Effect of Alpha Agonist on Resting Anal Pressure

Preparations of phenylephrine hydrochloride and oxymetazoline wereprepared. The oxymetazoline was first dissolved in propylene glycol andthen added to polyethylene glycol 1500 to obtain a solution in theconcentration of 1 mg/1 mL.

The preparations were administered intraanally. The doses are expressedas both a volume of a concentration of the drug solution and also asmilligrams of the active ingredient.

Resting anal pressure was determined by anorectal manometry formeasuring contractility in the anus and rectum using the ManoScan 360™catheter (Sierra Scientific Instruments).

Healthy volunteers, men and women of 18 to 55 years old receivedintraanal dose of 40 mg (40 mL) or 80 mg (80 mL) phenylephrine or a doseof 1 mg oxymetazoline (1 mL; 0.1%). None of the volunteers had symptomsof anal incontinence nor previous anal surgery and presumed to haveintact internal and external anal sphincters. Pre-treatment mean restingpressure was 85 mmHg for the phenyephrine 40 mg group, and 81 mmHg forthe phenylephrine 80 mg group.

After the application of the aforementioned doses of phenylephrine andoxymetazoline, resting anal pressure was determined at the followingtime intervals: for the phenyleohrine trial—prior to administration ofphenylephrine and 60, 120 and 240 minutes afterwards, and for theoxyetazoline trial—before administration and 60, 180 and 300 minutesafter application. The results are summarized in Tables 1 and 2 belowand in FIG. 1.

TABLE 1 Resting anal pressure upon administration of phenylephrine.Resting anal pressure Time (mmHg) Change Relative to T = 0 (min-Phenylephrine Phenylephrine Phenylephrine Phenylephrine utes) (40 mg)(80 mg) (40 mg) (80 mg) 0 85 81 0 0 90 95 103.5 10 22.5 180 92.5 87.757.5 6.75 240 83.25 80.25 0 (±1.75) 0 (±1.75)

TABLE 2 Resting anal pressure upon administration of oxymetazoline.Resting anal pressure Time (min.) (mmHg) Change Relative to T = 0 0 75 060 93 18 180 103 28 300 102 27

A pronounced increase in the maximum resting pressure, about 30 mmHgrelative to the pressure before treatment, was observed for treatmentwith oxymetazoline (FIG. 1). A smaller increase in anal pressure wasobtained with 80 mg phenylephrine (maximum increase of 22.5 mmHg) andmuch lower increase in pressure, with a maximum increase of 10 mmHg, wasobserved in the treatment with 40 mg phenylephrine.

The increased pressure obtained upon treatment with oxymetazoline wasmaintained for the duration of the recording, i.e. for at least 5 hours.However, the increased pressure obtained with 80 mg phenylephrinedropped within 3 hours nearly to the pressure obtained prior totreatment. Additionally, in less than 5 hours, the resting anal pressuredropped down to the pressure observed prior to treatment.

Treatment with 40 mg phenylephrine reached a very low increase relativeto the pressure before the treatment (an increase of 10 mmHg) whichgradually dropped and reached the initial (pre-treatment) resting analpressure within less than 5 hours.

The results highlight the superiority of oxymetazoline on phenylephrine.Oxymetazoline, at a low dose of 1 mg, induced a better effect (a markedincrease in resting anal pressure) which was maintained for a long time(for at least 5 hours), as compared to the effect exerted byphenylephrine at doses as high as 40 mg and 80 mg.

Example 2 The Cardiac Effect of Oxymetazoline

The effect of oxymetazoline on cardiac parameters was examined in fourhealthy human subjects. The results are presented in the Table 3.

TABLE 3 Resting anal pressure and cardiac parameters PhysiologicalOxymetazoline dose parameter 0.01% 0.1% 0.5% Change in resting 11 18.524.75 anal pressure (mmHg) Change in diastolic 2 0 1 blood pressure(mmHg) Change in heart rate −3 0 1 (beats/min) Change in systolic 6 5 3Blood pressure (mmHg)

The change in resting anal pressure with respect to baseline, inresponse to doses of 0.1% and 0.5%, was statistically significant.

The results indicate that at the low doses of oxymetazoline are highlyeffecting in inducing a significant increase in the resting analpressure, these doses do not induce any cardiovascular side effect.

The foregoing description of the specific embodiments will so fullyreveal the general nature of the invention that others can, by applyingcurrent knowledge, readily modify and/or adapt for various applicationssuch specific embodiments without undue experimentation and withoutdeparting from the generic concept, and, therefore, such adaptations andmodifications should and are intended to be comprehended within themeaning and range of equivalents of the disclosed embodiments. It is tobe understood that the phraseology or terminology employed herein is forthe purpose of description and not of limitation. The means, materials,and steps for carrying out various disclosed functions may take avariety of alternative forms without departing from the invention.

What is claimed is:
 1. A method comprising: administering inside theanal cavity of a patient a pharmaceutical composition comprisingoxymetazoline or a pharmaceutically acceptable salt or derivativethereof as an active ingredient, wherein a concentration of the activeingredient is within a therapeutically effective range of 0.05% to 1% totreat fecal incontinence.
 2. The method of claim 1, wherein the activeingredient is oxymetazoline hydrochloride.
 3. The method of claim 1,wherein the composition further comprises at least one carrier, diluent,excipient or combinations thereof.
 4. The method of claim 1, wherein thepharmaceutical composition is selected from the group consisting of:long acting, controlled release, slow release, sustained release,bioadhesive and mucoadhesive.
 5. The method of claim 1, wherein thepharmaceutical composition is in a dosage form selected from the groupconsisting of: gel, cream, paste, spray suppository, mousse, emollient,powder, solution, suspension and foam.
 6. The method of claim 1, whereinto treat fecal incontinence refers to reducing or preventing fecalincontinence, increasing the resting anal pressure of the patient,maintaining a high resting anal pressure for at least one hour of thepatient, and strengthening the anal sphincter muscles of the patientthereby preventing leakage and improving the rectum sensation.
 7. Themethod of claim 1, wherein the concentration of the active ingredient iswithin the range of 0.08 to 0.8%.
 8. The method of claim 1, wherein thepatient is effectively treated for fecal incontinence for at least 4hours.
 9. A kit comprising: (a) a first dosage form comprising as soleactive ingredient oxymetazoline or a pharmaceutically acceptable salt orderivative thereof, wherein a concentration of oxymetazoline in thefirst dosage form is within a therapeutically effective range of 0.05 to1% to treat fecal incontinence; and (b) means for storing the dosageform.
 10. The kit of claim 9 further comprising a second dosage formcomprising a therapeutic agent selected from the group consisting of: NOsynthase inhibitor, prostaglandin F2a, dopamine, morphine, loperamide,β-blockers, sodium valproate, codeine phosphate and 5-Hydroxytryptamine.11. The kit of claim 9, wherein the first dosage form and the seconddosage form are contained in separate containers.
 12. The kit of claim9, wherein the first dosage form comprises oxymetazoline hydrochloride.13. A pharmaceutical composition comprising: a gel consistingessentially of oxymetazoline or a pharmaceutically acceptable salt orderivative thereof as an active ingredient, wherein a concentration ofthe active ingredient is within a therapeutically effective range of0.05% to 1% to treat fecal incontinence.
 14. The pharmaceuticalcomposition of claim 13, wherein the active ingredient is oxymetazolinehydrochloride.
 15. The pharmaceutical composition of claim 13, whereinthe composition further comprises at least one carrier, diluent,excipient or combinations thereof.
 16. The pharmaceutical composition ofclaim 13, wherein the pharmaceutical composition is selected from thegroup consisting of: long acting, controlled release formulation, asustained release formulation, bioadhesive formulation, mucoadhesiveformulation, and a slow release formulation.
 17. The pharmaceuticalcomposition of claim 13, wherein the concentration of the activeingredient is within the range of 0.08 to 0.8%.
 18. The pharmaceuticalcomposition of claim 13, wherein the pharmaceutical composition afterbeing administered to a patient is effective for treating the patientfor fecal incontinence for at least 4 hours.
 19. The method of claim 1,wherein the pharmaceutical composition consists of oxymetazoline or apharmaceutically acceptable salt or derivative thereof as an activeingredient.
 20. The pharmaceutical composition of claim 13, wherein thepharmaceutical composition consists of oxymetazoline or apharmaceutically acceptable salt or derivative thereof as an activeingredient.